Schizophrenia, which is characterized by the change of basic personality, the schism of thinking, feeling and behavior, and the disharmony of psychomotility and surroundings, is a most common type of mental illness and belongs to the severe type. Schizophrenia mainly occurs in young and middle-aged people without organic change, and it is a functional psychosis. Patients suffering from schizophrenia generally have no impediment in consciousness and intelligence, but when there is schizophrenic attack, it not only affects the labor capacity of the patients, but also exerts great influence on working, studying, living and socializing of the patients themselves. Medication therapy is one of the most commonly-used and effective treatment methods so far, and it can not only effectively control the schizophrenic symptoms, but also significantly control and reduce the frequency and intensity of the onset of the disease.
Antipsychotics are usually classified into two categories of typical and atypical according to the mechanism of action: (1) typical antipsychotics (traditional antipsychotics), whose representatives include chloropromazine, haloperidol and the like; (2) atypical antipsychotics (nontraditional antipsychotics), whose representatives include paliperidone, clozapine, risperidone and the like. Compared with the traditional medicines, the atypical antipsychotics have lower affinity with dopaminergic D2 receptor, but have higher affinity with 5-hydroxytryptamine and noradrenergic receptor. Meanwhile, atypical antipsychotics have broad treatment spectrum and significant effect on negative symptoms when compared to traditional medicines, and they have high security, fewer adverse effect and low dosage, significantly improving the compliance of the patients.
Paliperidone (9-hydroxyrisperidone), which is a benzoisoxazole derivative, is a new type of antipsychotic, and the exact mechanism of action thereof is still unclear. It is now thought that paliperidone blocks the signal transmission of neurotransmitters in brain of the patients by blocking dopaminergic (D), 5-hydroxytryptamine-2A (5HT2) and adrenergic receptors. Paliperidone has an oral bioavailability of 28%, a plasma protein binding rate of 74%, a half-life of the terminal elimination phase of about 23 h, and an apparent volume of distribution of 487 L. The major adverse effects after oral administration of paliperidone include anxiety, somnolence, dizziness, constipation, extrapyramidal symptoms and the like.
U.S. Pat. Nos. 5,158,952; 4,804,663; 4,352,811 and 4,458,076 describe in detail the paliperidone compound and preparation process thereof.
Chinese patent publication No. CN101,264,084 provides a method for the treatment of psychiatric patients having or at risk of hepatic impairment, which comprises administering a therapeutically effective dose of paliperidone, its pharmaceutically acceptable acid addition salts, enantiomer and esters thereof to psychiatric patients in need thereof.
In the international application Nos. WO 00/35419, WO 96/31201, WO 01/34120 and U.S. Pat. Nos. 5,654,008; 5,650,173; 5,770,231; 6,077,843; 6,368,632; 6,110,923; 5,695,168; 5,692,477; 5,871,778; 5,656,299, paliperidone is used as the model drug to prepare various dosage forms such as liquid gelatin capsule, transdermal patch, long-acting injection implant and the like, but the preparation of osmotic pump controlled release tablet using paliperidone is not disclosed.
Osmotic pump controlled release tablet is an oral controlled release drug delivery system based on osmosis, which is a general technology for the preparation of sustained/controlled release dosage form. U.S. Pat. Nos. 3,845,770; 3,916,899; 3,995,631; 4,008,719; 4,160,020; 4,034,758; 4,327,725; 4,578,075; 4,681,583; 4,783,337; 5019397; 5,156,850 describe the osmotic pump controlled release technology in detail, which are incorporated herein by reference. Osmotic pump controlled release dosage form usually has the following advantages: (1) it possesses a preset drug-release kinetic behavior; (2) it is less influenced by the factors such as pH of the medium, gastrointestinal peristalsis and food; and has a good relevance between in vivo and in vitro; (3) it is capable of avoiding the phenomenon of large fluctuation range of blood concentration caused by common oral dosage forms; (4) it is capable of reducing the frequency of administration, and improving the compliance of patients.
On the basis of above advantages of the osmotic pump controlled release tablet, paliperidone may be combined with the osmotic pump controlled release drug delivery system to prepare paliperidone osmotic pump controlled release tablet, as a preferred oral osmotic (OROS) dosage form, so as to further reduce the neural adverse reactions (mainly extrapyramidal symptoms) of atypical antipsychotics, to decrease the fluctuation of blood concentration, to increase therapeutic effect, and to improve the compliance of patients.
At present, a commercially available paliperidone sustained release tablet (trade name: Invega) is a benzoisoxazole antipsychotic developed by Janssen L P, a member of Johnson & Johnson, US, and it was approved by FDA for marketing on Nov. 29, 2005, which was indicated for the treatment of schizophrenia and bipolar mania.
Chinese patent publication No. CN1,684,670A discloses a dosage form of substantially releasing paliperidone and preparation method thereof. The sustained release dosage form provides a therapeutically effective plasma concentration of paliperidone when administered once daily. The capsule-shaped sustained release tablet containing paliperidone of the invention is orally administered to release paliperidone at a substantially ascending release rate during the prolonged period of time. This invention describes in detail the preparation method of paliperidone capsule-shaped osmotic pump controlled release tablet, the main excipient of the tablet core is a polymeric material—polyoxyethylene. Unfortunately, however, we have found that the three-layered capsule shaped osmotic pump controlled release tablet still has some disadvantages for the following reasons, for example:
(1) It needs a special preparation process with a high production cost. The preparation process of the three-layered osmotic pump controlled release tablet is comparatively complicated, wherein it requires to prepare two kinds of drug layer particles with different drug contents and determined respectively the drug content, and then press into tablet, and thus the preparing period is long with more workload. The common used doses of paliperidone include 3 mg, 6 mg, and 9 mg, which belong to the low dose drug, and thus paliperidone has high requirements for content uniformity of the tablet core. But for a three-layered tablet, it is more difficult to achieve a satisfactory content uniformity Therefore, the preparation of a three-layer capsule shaped osmotic pump controlled release tablet requires a specific tablet compressor (three-layered tablet press), with a higher machining precision.
(2) The main excipient for tablet core has a poor thermal stability. Polyoxyethylene is a kind of high molecular polymer with poor thermal stability and which has low glass transition temperature (62˜67° C.). Due to the above features, it has the following problems during the industrial production and storage. (i) It is difficult to dry off the solvent during granulation process. The drying temperature for polyoxyethylene is generally less than 40° C., thus easily leading to problems of insufficient dryness and high residue of organic solvent; and if a complete dryness is required, it requires a relatively long drying duration, which results in higher production cost. (ii) The storage temperature of the tablet should not be too high, and the tablet has to be stored in a cool, dark place, which increases the storage cost. Meanwhile, a high storage temperature tends to cause some changes in the physicochemical properties of polyoxyethylene, such as, the oxidative degradation of polyoxyethylene, the decrease in the viscosity of the tablet core, which eventually result in the acceleration of the release of the controlled release tablet, and this will increase potentially dangerous factors to the treatment of patients. (iii) During high-speed tablet pressing, the punch die repeatedly rubs to generate heat, and when the temperature reaches about 50° C., phenomena such as sticking, rough appearance of tablet core, rolled edge in part of the tablet core would likely appear. Therefore, it usually requires a special cooling equipment to control the temperature of punch die. For the osmotic pump controlled release tablet, the rolled edge in part of the tablet core is likely to cause vulnerable point in the coating membrane in the said part, which may lead to the fracture of the coating membrane in the course of release. Consequently, it affects the release rate of the drug, and more seriously, a sudden release of the drug caused by the fracture of the coating membrane may directly contribute to the fluctuation of blood concentration, thus increase the potential risk and adverse reaction of the administration of the psychotic patients, which goes against the purpose for preparing osmotic pump controlled release tablet.
(3) The three-layered capsule shaped osmotic pump controlled release system releases paliperidone at a substantially ascending release rate, which results in a relatively large fluctuation range of blood concentration, and thus reduces the safety, effectiveness and compliance of the administration.
Therefore, there is a need to provide a paliperidone osmotic pump controlled release tablet, which has a simple preparation process, low cost excipients for tablet core and good thermal stability, and is capable of effectively control the release rate of the drug to keep the curve of blood concentration smooth and reduce its fluctuation, and thus improve safety, effectiveness and compliance of the administration.